Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency

Kathryn J. Griffin*, Laura M. Newell, Kingsley R. Simpson, Cora M.L. Beckers, Mark J. Drinkhill, Kristina F. Standeven, Lih T. Cheah, Siiri E. Iismaa, Peter J. Grant, Christopher L. Jackson, Richard J. Pease

*Corresponding author for this work

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Abstract

Background and aims: 

Transglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. 

Methods: 

Atherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases. Cardiac fibrosis was assessed both in the mixed strain mice and also in C57BL/6J Apoe expressing mice lacking either or both transglutaminases. 

Results: 

No difference was found in the density of buried fibrous caps within brachiocephalic plaques from mice expressing or lacking these transglutaminases. Cardiac fibrosis developed in both Apoe/F13a1 double knockout and F13a1 single knockout mice, but not in Tgm2 knockout mice. However, concomitant Tgm2 knockout markedly increased fibrosis, as apparent in both Apoe/Tgm2/F13a1 knockout and Tgm2/F13a1 knockout mice. Amongst F13a1 knockout and Tgm2/F13a1 knockout mice, the extent of fibrosis correlated with hemosiderin deposition, suggesting that TG2 limits the extravasation of blood in the myocardium, which in turn reduces the pro-fibrotic stimulus. The resulting fibrosis was interstitial in nature and caused only minor changes in cardiac function. 

Conclusions: 

These studies confirm that FXIII-A and TG2 fulfil different roles in the mouse myocardium. FXIII-A protects against vascular leakage while TG2 contributes to the stability or repair of the vasculature. The protective function of TG2 must be considered when designing clinical anti-fibrotic therapies based upon FXIII-A or TG2 inhibition.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalAtherosclerosis
Volume294
Early online date17 Dec 2019
DOIs
Publication statusPublished - 1 Feb 2020

Keywords

  • Atherosclerosis
  • Factor XIII-A
  • Fibrosis
  • Myocardium
  • Transglutaminase 2

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    Griffin, K. J., Newell, L. M., Simpson, K. R., Beckers, C. M. L., Drinkhill, M. J., Standeven, K. F., Cheah, L. T., Iismaa, S. E., Grant, P. J., Jackson, C. L., & Pease, R. J. (2020). Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency. Atherosclerosis, 294, 1-9. https://doi.org/10.1016/j.atherosclerosis.2019.12.013